1. Population pharmacokinetic and pharmacodynamic modeling of different formulations of ONO-5334, cathepsin K inhibitor, in Caucasian and Japanese postmenopausal females.
- Author
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Hasegawa, Chihiro, Ohno, Tomoya, Umemura, Takeo, Honda, Naoki, Ohyama, Michiyo, Nagase, Shinichi, Small, Maria, Deacon, Steve, Ogawa, Mikio, and Ieiri, Ichiro
- Subjects
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ASIANS , *BIOMARKERS , *BONE resorption , *ENZYME-linked immunosorbent assay , *MOLECULAR structure , *OSTEOPOROSIS , *PROTEOLYTIC enzymes , *RESEARCH funding , *WHITE people , *RANDOMIZED controlled trials , *BLIND experiment , *POSTMENOPAUSE , *DATA analysis software , *DESCRIPTIVE statistics , *INVESTIGATIONAL drugs , *CHEMICAL inhibitors , *PHARMACODYNAMICS - Abstract
ONO-5334, a selective inhibitor of cathepsin K, is a potential new treatment for osteoporosis. The objectives of this study were to (1) develop population pharmacokinetic-pharmacodynamic (PK-PD) models for ONO-5334 using dose-ascending data from healthy postmenopausal females, (2) examine comparability of PK and/or PD profile between Caucasian and Japanese, and (3) compare PK-PD profile between immediate release tablet (IRT) and sustained release tablet (SRT). The population PK-PD models were developed for each formulation for post-dose levels of bone resorption markers (serum CTX and NTX). The data were provided from 4 phase 1 studies with total of 201 Caucasian and 94 Japanese subjects. Plasma concentrations of ONO-5334 and bone resorption markers were thoroughly evaluated in those studies. An indirect response model described relationships between bone resorption markers and plasma concentrations of ONO-5334. There was no significant difference in PK and pharmacodynamic potency (IC50) between Caucasian and Japanese. Based on the developed model, serum CTX and NTX after administration of ONO-5334 IRT or SRT were simulated, and the results showed that ONO-5334 SRT would provide comparable PD effect on bone resorption markers with lower dose relative to IRT. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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